title: Whole-exome sequencing identifies a variant of the mitochondrial MT-ND1 gene associated with epileptic encephalopathy: west syndrome evolving to Lennox-Gastaut syndrome.
abstract: We describe a West syndrome (WS) patient with unidentified etiology that evolved to Lennox-Gastaut syndrome. The mitochondrial respiratory chain of the patient showed a simple complex I deficiency in fibroblasts. Whole-exome sequencing (WES) uncovered two heterozygous mutations in NDUFV2 gene that were reassigned to a pseudogene. With the WES data, it was possible to obtain whole mitochondrial DNA sequencing and to identify a heteroplasmic variant in the MT-ND1 (MTND1) gene (m.3946G>A, p.E214K). The expression of the gene in patient fibroblasts was not affected but the protein level was significantly reduced, suggesting that protein stability was affected by this mutation. The lower protein level also affected assembly of complex I and supercomplexes (I/III2 /IV and I/III2 ), leading to complex I deficiency. While ATP levels at steady state under stress conditions were not affected, the amount of ROS produced by complex I was significantly increased.
authors.affiliation: Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, E-28041, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, Madrid, E-28041, Spain.
authors.forename: Aitor
authors.initials: A
authors.lastname: Delmiro
authors.forename: Henry
authors.initials: H
authors.lastname: Rivera
authors.forename: María Teresa
authors.initials: MT
authors.lastname: García-Silva
authors.forename: Inés
authors.initials: I
authors.lastname: García-Consuegra
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-Hernández
authors.forename: Pilar
authors.initials: P
authors.lastname: Quijada-Fraile
authors.forename: Rogelio Simón
authors.initials: RS
authors.lastname: de Las Heras
authors.forename: Ana
authors.initials: A
authors.lastname: Moreno-Izquierdo
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Martín
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arenas
authors.forename: Francisco
authors.initials: F
authors.lastname: Martínez-Azorín
mesh_terms: D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D065768:Lennox Gastaut Syndrome; D008969:Molecular Sequence Data; D009154:Mutation; D009245:NADH Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D013036:Spasms, Infantile / Q000235:genetics* / Q000378:metabolism
chemical_list: D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human
keywords: Lennox-Gastaut syndrome; MT-ND1or MTND1; ROS; West syndrome